chr12-2679713-G-A

Position:

• chr12-2679713-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000719.7(CACNA1C):​c.5361G>A​(p.Thr1787Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.694 in 1,608,514 control chromosomes in the GnomAD database, including 398,256 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (28886 hom., cov: 34)
  • Exomes 𝑓: 0.71 (369370 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.82

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 12-2679713-G-A is Benign according to our data. Variant chr12-2679713-G-A is described in ClinVar as [Benign]. Clinvar id is 93413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679713-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.721 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5595G>A	p.Thr1865Thr	synonymous_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5328G>A	p.Thr1776Thr	synonymous_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5526G>A	p.Thr1842Thr	synonymous_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5505G>A	p.Thr1835Thr	synonymous_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5484G>A	p.Thr1828Thr	synonymous_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5451G>A	p.Thr1817Thr	synonymous_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5445G>A	p.Thr1815Thr	synonymous_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5436G>A	p.Thr1812Thr	synonymous_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5421G>A	p.Thr1807Thr	synonymous_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5418G>A	p.Thr1806Thr	synonymous_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5418G>A	p.Thr1806Thr	synonymous_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5418G>A	p.Thr1806Thr	synonymous_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5412G>A	p.Thr1804Thr	synonymous_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5403G>A	p.Thr1801Thr	synonymous_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5385G>A	p.Thr1795Thr	synonymous_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5385G>A	p.Thr1795Thr	synonymous_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5379G>A	p.Thr1793Thr	synonymous_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5361G>A	p.Thr1787Thr	synonymous_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5352G>A	p.Thr1784Thr	synonymous_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5328G>A	p.Thr1776Thr	synonymous_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87834 AN: 152028 Hom.: 28877 Cov.: 34

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.613

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.672

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.667

Gnomad FIN AF: 0.767

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.726

Gnomad OTH AF: 0.586

GnomAD3 exomes AF: 0.677 AC: 160515 AN: 236924 Hom.: 55999 AF XY: 0.683 AC XY: 88041 AN XY: 128962

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.706

Gnomad ASJ exome AF: 0.664

Gnomad EAS exome AF: 0.624

Gnomad SAS exome AF: 0.665

Gnomad FIN exome AF: 0.763

Gnomad NFE exome AF: 0.723

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.706 AC: 1028616 AN: 1456368 Hom.: 369370 Cov.: 61 AF XY: 0.706 AC XY: 511204 AN XY: 724000

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.696

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.598

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.758

Gnomad4 NFE exome AF: 0.731

Gnomad4 OTH exome AF: 0.671

GnomAD4 genome AF: 0.577 AC: 87853 AN: 152146 Hom.: 28886 Cov.: 34 AF XY: 0.581 AC XY: 43218 AN XY: 74394

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.672

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.666

Gnomad4 FIN AF: 0.767

Gnomad4 NFE AF: 0.727

Gnomad4 OTH AF: 0.589

Alfa AF: 0.681 Hom.: 18547

Bravo AF: 0.553

Asia WGS AF: 0.637 AC: 2211 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 13, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0040
DANN	Benign	0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1051375; hg19: chr12-2788879; COSMIC: COSV59695567; COSMIC: COSV59695567;